Arana A, Pottegard A, Kuiper J, Booth H, Reutfors J, Calingaert B, Lund LC, Crellin E, Schmitt-Egenolf M, Kaye J, Gembert K, Rothman K, Kieler H, Dedman D, Houben E, Gutierrez L, Hallas J, Perez-Gutthann S. Long-term risk of skin cancer and lymphoma in users of topical tacrolimus and pimecrolimus: final results from the extension of the cohort study Protopic Joint European Longitudinal Lymphoma and Skin Cancer Evaluation (JOELLE). Clin Epidemiol. 2021 Dec 29;2021(13):1141-53.

PURPOSE: Evidence is insufficient to infer whether topical calcineurin inhibitors (TCIs; tacrolimus and pimecrolimus) cause malignancy. The study objective was to estimate the long-term risk of skin cancer and lymphoma associated with topical TCI use in adults and children, separately.

PATIENTS AND METHODS: A cohort study in Denmark, Sweden, UK, and the Netherlands was conducted. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for nonmelanoma skin cancer (NMSC), melanoma, cutaneous T-cell lymphoma (CTCL), non-Hodgkin lymphoma (NHL) excluding CTCL, and Hodgkin lymphoma (HL) in new users of TCIs versus users of moderate/high-potency topical corticosteroids.

RESULTS: The study included 126,908/61,841 adults and 32,605/27,961 children initiating treatment with tacrolimus/pimecrolimus, respectively. Follow-up was ≥ 10 years for 19% of adults and 32% of children. Incidence rate ratios and (95% confidence intervals) for tacrolimus versus corticosteroid users in adults were < 1 for melanoma, non-Hodgkin lymphoma, and Hodgkin lymphoma; and 1.80 (1.25– 2.58) for cutaneous T-cell lymphoma. For pimecrolimus, IRRs in adults were < 1 for non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and Hodgkin’s lymphoma; and 1.21 (1.03– 1.41) for melanoma; and 1.28 (1.20– 1.35) for nonmelanoma skin cancer. In children, results were inconclusive due to few events. In adults, incidence rate ratios ≥ 5 years after first topical calcineurin inhibitor exposure were not higher than in overall analyses.

CONCULSUION: Overall, we found little evidence associating use of topical calcineurin inhibitors with skin cancer and lymphoma; confounding by indication, surveillance bias, and reverse causation may have influenced these results. Even if causal, the public health impact of these excess risks would be low and confined to the first years of exposure.

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